We are interested in the circuitry of cellular signaling pathways and our long-term objective is to define which signaling connections are critical for tumor development. We are currently focusing our efforts on the mTOR network because numerous recent studies predict that deregulation of mTOR signaling is an important step in the pathogenesis of cancer. Collectively, these studies argue that the mTOR protein kinase receives regulatory signals from many diverse inputs and subsequently transmits these signals to a wide array of effectors. Based on these studies, a prototype mTOR-inhibitor has been propelled into clinical trials as an anti-cancer therapeutic, although it is still not clear how that inhibitor works or what the relevance of mTOR is to tumor formation. In this proposal, our goal is to define the critical roles of mTOR in cancer. In the mentored phase, we combine genetics, biochemistry, and RNAi technology to investigate the role of mTOR in general tumorigenesis. This phase is designed to provide extensive supervised training necessary for transitioning to and independent research position. In the independent phase, we (1) investigate the role of mTOR in specific cancers, (2) determine the key mTOR-derived signals relevant in cancer, and (3) use novel lentiviral-based RNAi technologies to search for potential anti-cancer drug targets. We believe our study will shed light on the relevance of mTOR in human cancer and help to design strategies for inhibiting mTOR signaling as a treatment for cancer patients. Emerging evidence indicates that aberrant regulation of a protein called mTOR is a critical step in the pathogenesis of cancer. In this proposal, we take a multidisciplinary approach that exploits state-of-the-art in vitro and in vivo technologies to (1) study the role of mTOR in cancer and (2) to foster development of mTOR-based therapeutics. Because mTOR- inhibitors are speculated to be promising anti-cancer therapeutics and this is attracting large investments from the pharmaceutical industry, our study is designed to provide important information regarding the rational development and use of such drugs.